Effect of P2Y12 Inhibitors on Organ Support–Free Survival in Critically Ill Patients Hospitalized for COVID-19

Key Points Question What is the effect of P2Y12 inhibition, a proposed therapeutic target and preventive strategy, on clinical outcomes in critically ill patients hospitalized for COVID-19? Findings In this randomized clinical trial that included 949 participants, use of a P2Y12 inhibitor did not result in a greater number of days alive and free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. Meaning These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19.


Endpoint Definitions
The full list of secondary endpoints is available in the trial protocol. The CEC will consider for adjudication all cases of the following: • Death due to cardiovascular, non-cardiovascular, and undetermined cause Deep Venous Thromboembolism The diagnosis of definite symptomatic deep venous thromboembolism (DVT) requires symptoms of venous thromboembolism with at least one of the following: • Abnormal compression ultrasound consistent with DVT or abnormal flow pattern or direct clot visualization in veins not amenable to compression. • One or more new filling defects by venography, CT venography, or MR venography.
• Abnormal compression ultrasound where compression had been normal or, if known to be noncompressible, a substantial increase (≥4mm) in the diameter of a previously non-compressible venous segment. The diagnosis of presumed deep venous thromboembolism requires the following: • In the absence of objective testing, high pre-test probability according to investigator assessment o OR adjudicator's gestalt o OR Wells score f • AND a treatment plan for DVT was initiated (initiation of anticoagulation, or escalation of anticoagulation dose, frequency, or duration).

Pulmonary Embolism
The diagnosis of definite pulmonary embolism requires at least one of the following: • New intraluminal filling defect at CT pulmonary angiography in a subsegmental or larger vessel.
• New intraluminal filling defect, or an extension of an existing defect, or a new sudden cut-off of vessels > 2.5 mm in diameter at pulmonary angiogram • Inconclusive CT pulmonary angiography, pulmonary angiography, or VQ scan evidence of a new or recurrent PE with demonstration of a new or recurrent DVT in the lower extremities by compression ultrasonography or venography. [4,5] • New clot or intraluminal filling defect noted in the right heart ("clot in transit") or the pulmonary vasculature at echocardiogram • High probability (revised PIOPED criteria) on planar ventilation/perfusion (V/Q) scan OR positive PE on SPECT ventilation perfusion (V/Q) scan. The diagnosis of presumed pulmonary embolism requires the following: Clinical signs and symptoms of pulmonary embolism, including but not limited to dyspnea, cough, hypoxemia, tachycardia, appropriate electrocardiographic changes, or evidence of right heart strain on echocardiogram; AND chest CT or pulmonary angiography are unable to be performed AND therapeutic dose anticoagulation or fibrinolytic therapy is prescribed by a physician

Arterial Thromboembolism
The diagnosis of arterial thromboembolism is defined as the following: • A clinical history and presentation consistent with a sudden significant worsening of end organ or limb perfusion AND EITHER • Confirmation of arterial obstruction by imaging, hemodynamics, intraoperative findings, or pathological evaluation OR • Requirement for thrombolysis, thrombectomy, or urgent bypass.
Note that arterial thromboembolism includes both acute in situ thrombotic events and acute embolic events. Note that while ischemic stroke and myocardial infarction can be arterial thromboembolic events, those events will be adjudicated according to the separate standardized criteria included below.
Myocardial Infarction COVID-19 patients are well known to have elevations in cardiac troponin concentrations, and these elevations often do not represent arterial thrombosis and downstream myocardial ischemia. Therefore, the CEC will make an effort to distinguish true myocardial infarction from coronary artery obstruction, typically from atherothrombosis (usually considered a "type 1 myocardial infarction") from myocardial infarction due to demand ischemia (usually defined as a "type 2 myocardial infarction") and myocardial injury (an elevation in cardiac troponin typically without symptoms of chest pain or signs of arterial thrombosis). These definitions will be consistent with the 4 th Universal Definition of Myocardial Infarction and will take into considerations suggestions made about classification of certain conditions as type 1 as compared to type 2 myocardial infarction. Regional coronary venous thrombosis with associated regional myocardial infarction has been reported in COVID. If this mechanism is documented, these will be considered a type 1 MI. The trial and CEC are focused on ascertaining and Figure 1. Model for interpreting myocardial injury. [1] adjudicating cases of acute myocardial injury and acute myocardial infarction and classifying those cases as described below. COVID also causes microvascular thrombi which are associated with patchy myocardial necrosis. These will be grouped with myocardial injury.

Figure 2. Table from the 4 th Universal Definition of Myocardial Infarction summarizing the different definitions of myocardial injury and infarction. [1]
Myocardial Injury: The increasing sensitivity of cardiac troponin (cTn) assays means that ongoing myocardial injury is frequently detected. Myocardial injury is a prerequisite for myocardial infarction (MI), but as noted below, criteria in addition to myocardial injury are necessary to make the diagnosis of MI. Adjudicators must distinguish between acute myocardial injury that is not secondary to ischemia but may be due to other conditions (Table 1).
Criteria for Myocardial Injury: Detection of an elevated cTn value above the 99 th percentile upper reference limit (URL) is defined as myocardial injury. The injury is considered acute if there is a rise and/or fall of cTn values. [1] Criteria for Procedure Related Myocardial Injury: Cardiac procedural myocardial injury is arbitrary defined by increased in cTn values (>99 th percentile URL) in patients with normal baseline values (<99 th percentile URL) or a rise of cTn values >20% of the baseline value when it is the above the 99 th percentile URL but is stable or falling.
Myocardial Infarction Type 1: Detection of rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia with at least one of the following: • Symptoms of ischemia • New ischemic ECG changes indicative of new ischemia (new ST-T changes or new LBBB) * • Development of pathological Q waves in the ECG** • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology • Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy † • *ECG manifestation of acute myocardial ischemia (in the absence of LVH and LBBB): o ST Elevation: New ST elevation at the J-point in two contiguous leads with the cut-point: ≥ 1 mm in all leads other than leads V2-V3, where the following cut-points apply: ≥2mm in men ≥40 years; ≥2.5 mm in men <40 years; or ≥ 1.5 mm in women regardless of age. o ST-depression and T-wave changes: New horizontal or down-sloping ST depression ≥ 0.5 mm in 2 contiguous leads and/or T inversion ≥ 1 mm in two contiguous leads with prominent R waves or R/S ratio >1. • **Pathological Q waves: o Any Q-wave in leads V2-V3 >0.02 seconds or QS complex in leads V2-V3 o Q-wave ≥ 0.03 seconds and ≥1 mm deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any 2 leads of a contiguous lead grouping (I, aVL;V1-V6; II, III, aVF; V7-V9). o R-wave ≥ 0.04s in V1-V2 and R/S ≥ 1 with a concordant positive T-wave in the absence of a conduction defect • †Postmortem demonstration of an atherothrombosis in the artery supplying the infarcted myocardium, or a macroscopically large, circumscribed area of necrosis with or without intramyocardial hemorrhage meets the type 1 MI criteria regardless of cTn values. • Consideration will be given to recent proposals to modify myocardial infarction type 1 to include coronary obstruction by spontaneous coronary artery dissection, coronary embolism, or coronary vasospasm or microvascular dysfunction. [5]  Myocardial Infarction Type 2: Detection of a rise and/or fall of cTn values with at least 1 value above the 99 th percentile URL, and evidence of imbalance between myocardial oxygen supply and demand unrelated to coronary atherothrombosis, requiring at least 1 of the following: • Symptoms of acute myocardial ischemia • New ischemic ECG changes • Development of pathological Q waves; • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with ischemic etiology Myocardial Infarction Type 3: Patients who suffer cardiac death, with symptoms suggestive of myocardial ischemia accompanied by presumed new ischemic ECG changes or ventricular fibrillation but die before blood samples for biomarkers can be obtained, or before increases in cardiac biomarkers can be identified, or MI is detected by autopsy examination.

Myocardial infarction Type 4a and 4b (myocardial infarction associated with percutaneous coronary intervention):
Criteria for percutaneous coronary intervention (PCI)-related MI ≤48 hours after the index procedure are as follows: Coronary intervention-related MI is arbitrarily defined by an elevation of cTn values >5 times the 99the percentile URL in patients with normal baseline values. In patients with elevated preprocedural cTn in whom the cTn levels are stable (≤20% variation) or falling, the post procedure cTn must rise by >20%. However, the absolute procedural value must still be at least 5 times the 99 th percentile URL. In addition, 1 of the following elements is required: • New ischemic ECG changes • Development of new pathological Q waves; note that the development of new pathological Q waves meets the criteria for procedure-related MI if the cTn values are elevated and rising but <5 times the 99 th percentile URL. • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology • Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or side branch occlusion/thrombus, disruption of collateral flow, or distal embolization. • Type 4a MI is an MI associated with PCI • Type 4b MI is an MI associated with stent/scaffold thrombosis Myocardial Infarction Type 4c: A type 4c MI is an MI associated with restenosis associated with prior PCI. Possible Type 4c MI is evaluated using the same criteria as Type 1 MI.

Myocardial Infarction Type 5:
Criteria of coronary artery bypass grafting (CABG)-related MI ≤ 48 hours after the index procedure. CABG-related MI is arbitrarily defined as elevation of cTn values >10 times the 99 th percentile URL in patients with normal baseline cTn values. In patients with elevated preprocedural cTn in whom cTn are stale (≤20% variation) or falling, the post procedure cTn must rise by >20%. However, the absolute postprocedural values must still be >10 times the 99 th percentile URL. In addition, one of the following elements is required: • Development of new pathological Q waves; note that the development of new pathological Q waves meets the criteria for procedure-related MI if the cTn values are elevated and rising but <10 times the 99 th percentile URL. • Angiographically documented new graft occlusion or new native coronary artery occlusion; • Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology Special or unusual circumstances: Further guidance on distinguishing myocardial injury from myocardial infarction in the context of non-cardiac surgery, heart failure, myocarditis, Takotsubo syndrome, kidney disease, and in critically ill patients, and myocardial infarction nonobstructive coronary arteries is included in the 4 th Universal Definition of MI. [1] Stroke The definition of stroke used here is drawn from the definitions proposed by Hicks et al. and Sacco et al. [6,7] Stroke is defined as the acute onset of focal neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction.
A stroke is the acute onset of a new persistent neurological deficit attributed to an obstruction in cerebral blood flow with no apparent nonvascular cause (e.g., tumor, trauma, infection). Available neuroimaging studies will be considered to support the clinical impression and to determine if there is a demonstrable lesion compatible with an acute stroke. To the extent possible, all strokes will be classified as ischemic, hemorrhagic, or unknown.
For the diagnosis of stroke, the following criteria should be fulfilled:

2.
Duration of a focal/global neurological deficit that is: • EITHER ≥ 24 hours, • OR < 24 hours if: • Resolution of symptoms is due to least one of the following interventions: 1. Pharmacologic: intravenous or intraarterial thrombolysis 2. Non-pharmacologic: (i.e., neuro-interventional procedure such as intracranial angioplasty) • OR available MRI clearly documents a new hemorrhage or infarct • OR available head CT clearly documents a new hemorrhage or infarct or excludes a mimic of stroke • OR the neurological deficit results in death. Ideally, at least one of should be present to confirm the diagnosis of stroke: • Confirmation by neurology or neurosurgery specialist • Brain imaging procedure (at least one of the following): CT scan, MRI scan, or cerebral vessel angiography • Lumbar puncture (i.e., spinal fluid analysis diagnostic of intracranial hemorrhage) If the acute focal signs represent a worsening of a previous deficit, these signs must persist for more than 24 hours and be accompanied by an appropriate new MRI or CT scan finding.
Strokes are sub-classified as follows: Ischemic (non-hemorrhagic): An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke but would also be listed as a major bleeding safety event. Hemorrhagic: An acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. Hemorrhage in the brain is documented by neuroimaging or autopsy or lumbar puncture. Note that subdural hematomas are intracranial hemorrhagic events and not strokes.
Undetermined: An acute episode of focal or global neurological dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction but with insufficient information to allow categorization as either ischemic or hemorrhagic.

Major Bleeding
Major bleeding is defined as acute clinically overt bleeding associated with one or more of the following (as per ISTH guidelines): [8][9][10] Decrease in hemoglobin of 2 g/dL or more; • Transfusion of 2 units or more of packed red blood cells; • Bleeding that occurs in at least one of the following critical sites: o